Process for the production of medicament formulations

ABSTRACT

A medicament compact is produced by placing loose powdered medicament in a mould having a longitudinal axis where a mandrel is positioned along the longitudinal axis of the mould compressing the medicament when a force parallel to the longitudinal axis is applied. The frictional force between the medicament and the mould and the frictional force between the medicament and the mandrel are opposite. Apparatus and compacted medicaments are also disclosed,

This application is a 371 of PCT/GB94/02214 dated Oct. 10, 1994.

This invention relates to a novel process for the production of acompacted body of powdered medicament, especially powdered inhalationmedicament, referred to herein as a "medicament compact", of the typedisclosed in European Patent 407028.

The administration by inhalation of medicaments in dry powder form iswell known. Devices for the metering and dispensing of measured doses ofmedicament from a reservoir have also been described previously, forexample, in UK Patent No. 2041763 and U.S. Pat. No. 2,587,215. Suchdevices typically comprise a medicament reservoir and a metering chamberwith a volume chosen such that, when filled, the chamber contains thedesired weight of medicament for one dose. Filling of the meteringchamber is generally accomplished under the influence of gravity, thechamber typically being located at the bottom of the reservoir. Suchdevices have the disadvantage that variations in the density of themetered powder can easily occur resulting in inaccurate or inconsistentdosing. The packing density of the powder may also depend on the weightof powder remaining in the reservoir, leading to a gradual reduction inthe dose delivered by the device. In addition, the dose metered isstrongly dependent on the orientation of the device.

European Patent 407028 discloses a device which overcomes thedisadvantages of other dry powder devices by the use of a metering meanswhich relies not on gravitational force to fill a metering chamber, buton abrasion of a compacted body of powdered medicament. This applicationcontemplated the use of hydraulic presses and the like in the productionof the medicament compacts.

Since the device of European Patent 407028 (in which the medicamentcompacts are adapted for use) functions by abrading a fixed volume ofthe medicament compact, it is important that the density of medicamentthroughout the compact is as uniform as possible. If the density isuniform then slices of medicament of the same thickness abraded from thecompact will contain the same amount of medicament, thus ensuring thatthe correct dosage of medicament is consistently administered to apatient.

Compacted bodies of powdered inhalation medicament are also disclosed inInternational Patent Applications WO 93/24165 and WO 94/14490. The laterapplication (published after the priority date of the presentapplication) contemplates methods involving isostatic compression ofelastic matrices, injection moulding of plastified masses, meltingprocesses and pressure diecasting for the production of such compactedbodies.

International Patent Application WO 94/00291, published after thepriority date of the present application, describes a process for makingannular compacted bodies of powdered medicament which involves theradial compaction of loose powdered medicament using an expandingmandrel.

We have now found a novel process for the production of medicamentcompacts which allows for the production of medicament compacts having amore uniform density than compacts produced by prior art processes andwhich overcomes or substantially mitigates the problems encountered inprocesses known from the prior art.

According to the invention we provide a process for the production of amedicament compact, which comprises the steps of:

a) placing loose powdered medicament in a mould having a longitudinalaxis,

b) positioning a mandrel along the longitudinal axis of the mould; and

c) compressing the medicament by applying a force parallel to thelongitudinal axis such that during compression the frictional forcebetween the medicament and the mould and the frictional force betweenthe medicament and the mandrel are in opposite directions parallel tothe longitudinal axis.

Steps a) and b) may be performed in either order or simultaneously,however, we prefer the mandrel to be positioned along the longitudinalaxis of the mould after the medicament has been placed in the mould.Positioning the mandrel along the longitudinal axis of the mould afterthe powder has been added ensures an even distribution of powder aroundthe mandrel, placing the powder in the mould after the mandrel has beeninserted is less likely to give an even distribution of powder.

It is preferable that the frictional force between the medicament andthe mould and the frictional force between the medicament and themandrel are in opposite directions parallel to the longitudinal axis forthe entirety of the compaction step c).

The frictional force between the medicament and the mould and thefrictional force between the medicament and the mandrel may be caused tobe in opposite directions parallel to the longitudinal axis, byperforming the process such that the mould and the mandrel move relativeto one another in a direction parallel to the longitudinal axis duringthe compression process. The mandrel is preferably slidably mountedalong the longitudinal axis of the mould. Relative movement can thus beachieved by fixing the position of the mandrel and moving the mould in adirection parallel to the longitudinal axis, or by fixing the positionof the mould and moving the mandrel.

Compaction of the powder contained in the mould is preferably effectedusing compaction means, e.g. a compaction sleeve, adapted to fit aroundthe mandrel and slide inside the mould, thereby providing a limitingwall for the area in which the powder is compacted. If the mandrel andthe compaction means are held stationary relative to one another duringthe compaction of the powder, then the distance moved by the mouldrelative to the mandrel during the compaction process will be equal toor greater than the difference in height between the loose and compactedpowder contained in the mould. In order to increase the distance movedby the mould relative to the mandrel during the compaction process, thecompaction means may also be moved relative to the mandrel, in the samedirection as, but to a lesser degree than, the mould.

Alternatively, increased relative movement of the mandrel and mould maybe achieved by moving the mandrel and the mould in opposite directionsduring the compaction process.

To ensure that the frictional force between the medicament and the mouldand the frictional force between the medicament and the mandrel are inopposite directions parallel to the longitudinal axis for the entiretyof the compaction step there should be no pre-compaction of the powderprior to the relative movement of the mould and the mandrel, i.e. thecompaction means should exert no force on the powder before the mouldand mandrel begin to move relative to one another.

By ensuring that the frictional force between the medicament and themould and the frictional force between the medicament and the mandrelare in opposite directions parallel to the longitudinal axis duringcompaction the process according to the invention has the surprisingadvantage that it produces medicament compacts having a more uniformdensity than compacts produced by prior art processes. Medicamentcompacts having a uniform density distribution are advantageous in thatsequential volumes of medicament abraded from the compact, e.g. by thedevice disclosed in European Patent 407028, will have similar masses,thus resulting in improved uniformity of dose administered to thepatient.

The process is also advantageous in that it allows medicament compactsto be produced in a single rather than a multi-step compactionprocedure, it also allows the production of longer compacts having amore uniform density distribution.

The powdered medicament is preferably metered into the mould, e.g. byweighing the desired amount of medicament. Alternatively, medicamentcompacts of the desired total mass may be produced by cutting to theappropriate length.

When the mandrel is positioned along the longitudinal axis of the mouldafter the loose powdered medicament is placed in the mould, the mandrelpreferably has a tapered end. Thus, during the powder filing step themandrel is fully, or preferably partially, retracted from the mould andonce the powder is in the mould it is pushed, tapered end first, throughthe powder displacing it from its original shape into a shape, e.g. anannulus, suitable for compaction.

Prior to compaction, it is preferable to level the surface of the powdercontained within the chamber defined by the mould and the mandrel. Thismay be done by vibrating the compaction assembly and/or using alevelling device. This ensures that the powder has settled to a levelheight, i.e. that the surface of the powder is even, it can also assistin removing trapped air from the powder and in breaking up aggregates ofpowder. Vibration of the assembly may be achieved using anelectro-magnetic or other vibrator. Vibration preferably occurs duringstep b) and starts before the mandrel is pushed fully through thepowder. Vibration is preferably applied to the mandrel. The frequency ofvibration may be in the range of 100 to 1000 Hz.

During vibration of the mould assembly it is desirable that any looseparts of the assembly should be held in position. This may beaccomplished using mechanical clamping means, spring force, or by usinga vacuum to hold such parts in place.

The pressure exerted by the compaction means will depend upon thedesired density of medicament in the compact (by density of medicamentwe mean the mass of medicament per unit volume). However, the compactionmeans typically exerts a pressure of from 60×10³ to 2000×10³ N.m⁻², forexample 900×10³ N.m⁻². The apparatus for performing the processaccording to the invention may be provided with a load sensor, e.g. aload cell, to measure the compaction force. The load sensor may bepositioned under the mould or on the compaction means.

The density of the medicament in the compacts produced according to theinvention will depend inter alia upon the medicament used. However, atypical compact may have a density of from 0.1 to 1.5 g/cm³. The densityof the medicament compacts produced according to the invention may bedetermined by weighing a fixed volume of medicament abraded from thecompact.

We prefer the medicament compact to be formed in a mould whichsubsequently forms all or part of the medicament reservoir of amedicament inhalation device. Thus, after compaction the compact andmould are in a form suitable for direct transfer to the inhalationdevice. By obviating the need to remove the compact from the mould priorto its insertion in the device, handling of the medicament compact, andhence the risk of contamination or loss of medicament through prematureabrasion, is reduced.

After production the compact may be transferred directly to theinhalation device from which it is to be administered, alternatively thecompacts may be packaged separately thus providing replacementmedicament reservoirs for the device from which they are to beadministered.

According to a further aspect of the invention we provide the novelapparatus described herein for carrying out the first aspect of theinvention.

Therefore, we provide an apparatus for the production of a medicamentcompact from loose powdered medicament which comprises:

a) a mould having a longitudinal axis adapted to receive loose powderedmedicament,

b) a mandrel adapted to be positioned along the longitudinal axis of themould; and

c) means for compressing the medicament by applying a force parallel tothe longitudinal axis such that during compression the frictional forcebetween the medicament and the mould and the frictional force betweenthe medicament and the mandrel are in opposite directions parallel tothe longitudinal axis.

The apparatus according to the invention may be made from any suitablematerials known to those skilled in the art. Suitable materials for themandrel include stainless steel e.g. 316 grade, teflon coated stainlesssteel, silicon nitride, polyphenyl sulphide (PBS), acetal co-polymer,and especially polybutylene terephthalate (PBT) e.g. PBT containing 20%polytetrafluoroethylene (PTFE). Suitable materials for the compactionmeans, e.g. the compaction sleeve, include stainless steel and acetalco-polymer.

The relative movement of the various parts of the apparatus may beachieved mechanically, employing e.g. electrical or hydraulic power.Suitable drive means include e.g. a stepper motor or servo motor.Separate drive means are preferably provided for the mould and thecompaction means. The drive means are preferably provided along thelongitudinal axis of the mould and should ideally be controllable tospeed, position, acceleration and deceleration. Typical drive speeds forthe compaction assembly are, for positioning the mandrel along thelongitudinal axis of the mould, 50 to 1000 mm/min; and, for compactingthe medicament, 5 to 5000 mm/min.

When the medicament compact is for use in a device as disclosed inEuropean Patent 407028 in which the metering means includes a helicalblade for abrading the medicament compact, the face of the compactionsleeve which contacts the medicament compact is preferably provided witha helical profile having a pitch equal to that of device blade.Providing this helical profile means that in use the compact does nothave to be "primed" by abrading several doses from it until the blade"beds-in", thus reducing wastage of medicament.

Medicament compacts produced according to the invention will generallybe annular, i.e. cylindrical with a cylindrical inner space. The radialthickness of the medicament in such a medicament compact is preferablyin the range of 0.2 to 20 mm, more preferably 0.5 to 5 mm, for example 2mm. The cylindrical inner space preferably has a diameter of more than10 mm and preferably less than 100 mm, for example 20 mm.

The length of the medicament compact will inter alia on its intended useand the number of doses of active ingredient it contains. Foradministration from a device as disclosed in European Patent ApplicationNo. 407028, a suitable length will be in the range 5 to 50 mm, e.g. 20mm.

Active ingredients which may be incorporated in compacts producedaccording to the invention include any active ingredients which areconventionally administered by inhalation in powdered form. Such activeingredients include drugs for use in the prophylactic or remedialtreatment of the range of conditions known as reversible obstructiveairways disease, e.g. asthma and bronchitis. Specific active ingredientswhich may be mentioned include salts of cromoglycic acid, e.g. sodiumcromoglycate; salts of nedocromil, e.g. nedocromil sodium; inhaledsteroids such as beclomethasone dipropionate, tipredane, budesonide andfluticasone; anticholinergic agents such as ipratropium bromide;bronchodilators, e.g. salmeterol, salbutamol, reproterol, terbutaline,isoprenaline and fenoterol, and salts thereof. If desired a mixture ofactive ingredients, for example, a mixture of sodium cromoglycate and abronchodilator, such as salbutamol, reproterol, isoprenaline,terbutaline, fenoterol or a salt of any one thereof, may be used.

Other active ingredients that may be mentioned include antihistamines,e.g. clemastine, pentamidine and salts thereof, acetyl-β-methylcholinebromide; peptide hormones, e.g. insulin and amylin; bradykininantagonists; PLA₂ inhibitors; PAF antagonists; lipoxygenase inhibitors;leukotriene antagonists; CNS active drugs, e.g. NMDA antagonists,glutamate antagonists, CCK agonists and antagonists; macrolidecompounds, e.g. FK 506, rapamycin, cyclosporin and structurally relatedcompounds; vitamins; vaccines, e.g. MMR vaccine and polio vaccine; andvectors for gene therapy, e.g. plasmids containing genes intended tocorrect genetic disorders such as cystic fibrosis.

The particles of active ingredient incorporated into the medicamentcompacts preferably have a mass median diameter in the range 0.01 to 15μm. We prefer that at least 80% w/w and preferably at least 90% w/w ofthe particles of active ingredient are less than 20 μm, more preferablyless than 10 μm, especially less than 7 μm in diameter. The proportionof particles of active ingredient having a diameter in the range 2 to 15μm is preferably more than 80% w/w.

The particulate active ingredient may be prepared by any suitabletechnique, as will be known to those skilled in the art. Suitabletechniques include milling, e.g. cone milling, or using a hammer orfluid energy mill; micronisation, spray drying and freeze drying.

The medicaments to be compacted according to the invention may comprisea solid pharmaceutically acceptable carrier substance in addition to anactive ingredient. The carrier preferably has an effective particle sizeof from 10 to 100 μm. The term "effective particle size" is used todenote the apparent particle size of a body without distinction as tothe number of individual particles which go to make up that body i.e. nodistinction is made between a single particle of given size and anagglomerate of the same size which is composed of finer individualparticles.

The solid pharmaceutically acceptable carrier in the medicament willgenerally be a non-toxic material chemically inert to the activeingredient but may, if so desired, also comprise larger particles of theactive ingredient. Examples of carriers which may be used in themedicament compacts include dextrans, glucose, mannitol and lactose. Aparticularly preferred carrier is crystalline lactose.

The particulate carrier may be prepared by grinding the carrier andsubsequently separating out the desired fraction by conventionalmethods, e.g. by air classification and sieving.

The medicament may be prepared by mixing the ingredients together in amixer, e.g. a planetary or other stirred mixer, prior to formation ofthe compact according to the process of the invention.

When the medicament comprises a solid carrier, we prefer the proportionof active ingredient to be from 0.1 to 70% w/w, more preferably from 0.1to 55% w/w, and especially from 5 to 50% w/w of the medicament.

The medicament compacts according to the invention may also containother ingredients such as flavouring agents, sweetening agents orcolourants.

Any conventional pharmaceutically acceptable flavouring agents may beused, particular flavouring agents which may be mentioned includevolatile oils, e.g. peppermint oil; and menthol. The proprietary productknown by the tradename Dentomint, which contains both peppermint oil andmenthol, may also be used. The flavouring agent may be a polysaccharideentrapped flavouring agent such as those disclosed in InternationalPatent Application WO 93/17663. Polysaccharide entrapped flavouringagents are advantageous for use in the compacts produced according tothe invention since they are sufficiently resilient to sustain thecompression forces required to produce the medicament compacts withoutreleasing the flavouring agent entrapped therein to any significantextent.

Sweetening agents which may be used include any conventional sweeteningagents, particular sweetening agents which may be mentioned includesaccharin sodium, mannitol, aspartame, cyclamates and sugar.

The medicament compacts produced according to the invention preferablycontain a plurality of doses of active ingredient. The actual number ofdoses incorporated into the compacts will depend inter alia upon thelength of the compact, the nature of the active ingredient and thedevice from which it is to be administered. However, the compacts willtypically comprises from 20 to 250, e.g. 112 doses of active ingredient.

The following non-limitative examples illustrate medicament compositionssuitable for compaction according to the present invention:

    ______________________________________                                        Ingredients           % w/w                                                   ______________________________________                                        Example 1                                                                     Nedocromil sodium (milled)                                                                          50                                                      Flavoured polysaccharide                                                                            5                                                       (85% maltodextrin:15% peppermint oil)                                         Lactose to            100                                                     Example 2                                                                     Nedocromil sodium (milled)                                                                          50                                                      Saccharin sodium      1.25                                                    Lactose to            100                                                     Example 3                                                                     Nedocromil sodium (milled)                                                                          50                                                      Flavoured polysaccharide                                                                            5                                                       (85% maltodextrin:15% peppermint oil)                                         Saccharin sodium      1.25                                                    Lactose to            100                                                     ______________________________________                                    

The invention will now be described, by way of example only, withreference to the accompanying drawings, in which:

FIG. 1 shows, in longitudinal section, the components of a compactionapparatus for performing the process according to the invention andtheir mode of assembly;

FIGS. 2A-2E show the stages involved in the production of a medicamentcompact using the apparatus of FIG. 1; and

FIGS. 3A-3C show schematically the stages involved in the production ofa medicament compact according to the invention in which the relativemovement of the mandrel and the mould is increased.

In the Figures corresponding features of the apparatus for performingthe alternative processes are given the same reference numeral.

Referring firstly to FIG. 1:

The compaction apparatus comprises a block (1) defining a cylindricalinner space. A cylindrical mandrel (2) having a tapered end is disposedwithin said inner space and slidably mounted within the block (1). Mould(3) comprising an open ended cylinder is located within block (1), suchthat mandrel (2) is free to slide along the longitudinal axis of themould (3). The inner surface of mould (3) and the outer surface ofmandrel (2) define the sides of the annular chamber within which themedicament powder is compacted, the bottom of this chamber being definedby a lip on the base of the mould (3).

In use, the block (1) is mounted in a housing (not shown) in which it isfree to move vertically. The mandrel (2) is held in the housing therebypreventing its movement relative to the housing.

Cover (4) having a bore identical to the bore of the mould (3) fits overthe mould (3) and is be held in position under the action of a spring. Aannular compaction sleeve (5), the bore of which is a close fit over themandrel (2) and the outside diameter of which is a close fit on theinside diameter of the cover (4) mould (3), is located within the boreof cover (4). The packing face (6) of the compaction sleeve (5), whichprovides the upper limiting wall to the chamber in which the medicamentpowder is compacted, has a helical profile.

Referring now to FIGS. 2A-2E which illustrate the production of amedicament compact:

Mould (3) is located into the cylindrical inner space of block (1) and aweighed quantity of powdered medicament (7) is placed in the mould (3).The medicament (7) is prevented from falling out of the bottom of mould(3) by the mandrel (2) the tapered end of which projects through thebase of the mould (3) s FIG. 2A.

Cover (4) and compaction sleeve (5) are then placed on the block (1) andheld in place by spring force--FIG. 2B.

The medicament (7) is distributed around the mandrel (2) by theapplication of vertical vibration to the mandrel (2). The vibration iscontinued as block (1), mould (3), cover (4) and compaction sleeve (5)are lowered around the mandrel (2) thus levelling the surface of thepowder before compaction. The vibration is then turned off--FIG. 2C.

The block (1), mould (3) and cover (4) are then lifted together whilstthe mandrel (2) and compaction sleeve (5) remain stationary. The packingface (6) of is the compaction sleeve (5) is thus urged against thepowdered medicament (7) contained in the mould (3) and the powderedmedicament (7) is thus compacted. During the compaction process thefrictional force between the medicament (7) and the mould (3) in adirection parallel to the longitudinal axis of the mould (3) is directedupwards towards the compaction sleeve (5), and the frictional forcebetween the medicament (7) and the mandrel (2) in a direction parallelto the longitudinal axis of the mould (3) is directed downwards towardsthe base of the mould (3). The degree of movement and hence thecompacted height of the medicament (7) is determined by the drive means(not shown) which is programmed for the particular compactionheight--FIG. 2D.

The cover (4) and compaction sleeve (5) are then lifted off the block(1). The mould (3) containing the compacted body of powdered medicament(8) can then be removed from the block (1) and assembled directly into amedicament inhalation device, the mould (3) being adapted to form all orpart of the medicament reservoir of the medicament inhalationdevice--FIG. 2E.

Referring now to FIGS. 3A-3C, which illustrate a compaction process inwhich the distance moved by the mould (3) relative to mandrel (2) isgreater than in the process shown in FIG. 2:

As in FIG. 2, a weighed quantity of powdered medicament (7) is placed inthe mould (3) around the tapered end of mandrel (2). Cover (4) andcompaction sleeve (5) are then fitted in place--FIG. 3A.

The block (1), mould (3), cover (4) and compaction sleeve (5) arelowered around the mandrel (2) which is held stationary. In this processthe mould (3) is lowered further around the mandrel (2) than in FIG. 2,so that the mandrel (2) projects inside the compaction sleeve (5)--FIG.3B.

Mould (3) and cover (4) are moved up the mandrel (2) together, at thesame time the compaction sleeve (5) is also moved upwards but through asmaller distance than the mould (3). Hence the mould (3) converges onthe compaction sleeve (5) and the powder (7) is compacted--FIG. 3C.

We claim:
 1. A process for the production of a medicament compact,comprising the steps of:a) placing loose powdered medicament in a mould(3) having a longitudinal axis, b) positioning a mandrel (2) along thelongitudinal axis of the mould (3); and c) compressing the medicament byapplying a force parallel to the longitudinal axis such that duringcompression the frictional force between the medicament and the mould(3) and the frictional force between the medicament and the mandrel (2)are in opposite directions parallel to the longitudinal axis.
 2. Aprocess according to claim 1, wherein the mould (3) and the mandrel (2)move relative to one another in a direction parallel to the longitudinalaxis during the compression process.
 3. A process, according to claim 2,wherein relative movement of the mould (3) and mandrel (2) is achievedby fixing the position of the mandrel (2) and moving the mould (3) in adirection parallel to the longitudinal axis during the compressionprocess.
 4. A process according to claim 1 in which the surface of thepowder is levelled prior to compaction.
 5. A process according to claim1, wherein the end of the mandrel (2) is tapered.
 6. A process accordingto claim 1, wherein the mandrel (2) is vibrated as it positioned alongthe longitudinal axis of the mould (3).
 7. A process according to claim1, wherein the powder is compacted by compaction means (5) having acompacting face provided with a helical profile (6).
 8. A processaccording to claim 1, wherein the medicament compact (8) is formed in amould (3) which subsequently forms all or part of a medicament reservoirof a medicament inhalation device.